The application is submitted in response to the Program Announcement (PAR-02-138) requesting applications for exploratory/developmental projects in translational research. This proposal seeks to identify candidate therapeutics for neurodegenerative disorders. We have recently discovered a small lipophilic cationic peptide DAPL (Dmt-D-Arg-Phe-Lys-NH2, where Dmt = 2', 6'-dimethyltyrosine) that is cell permeable and selectively targets mitochondria. Preliminary studies with isolated mouse liver mitochondria have shown that this small peptide can protect against mitochondrial permeability transition and swelling, and reduce accumulation of reactive oxygen species. By protecting against mitochondrial dysfunction, this peptide may potentially be useful in the treatment of numerous neurodegenerative disorders. We are now seeking short-term support to further explore the pharmacology of this lead peptide analog in protecting brain mitochondria against various mitochondrial toxins, and to discover new analogs of this peptide that might lead directly to a therapy development project for a particular neurological disorder. Our specific aims are as follows: 1) To examine the ability of DAPL to protect mitochondria dysfunction caused by calcium overloading, 3-nitropropionic acid (3NPA), 1-methyl-4-phenylpyridium ion (MPP+), and t-butyl hydroperoxide (tBHP; 2) To examine the ability of DAPL to protect against cell death caused by glutamate, 3NPA, MPP +, and tBHP; 3) To carry out structure-activity relationship (SAR) studies with DAPL analogs to identify the optimal peptide analog for further preclinical development. The results from these exploratory studies will guide us to the development of preclinical animal studies for evaluating the therapeutic potential of DAPL analogs in the treatment of stroke and various neurodegenerative disorders, including Parkinson's disease, Huntington's disease and Alzheimer's disease. Potential collaborators for the animal studies have already been identified.